Glaucoma is one of the three leading causes of blindness in the United States and a leading cause of blindness in the world. Over 2.2 million people in the United States have glaucoma, and several million more are at risk of developing the disease. As the population ages, the number of individuals with glaucoma will continue to grow since glaucoma affects the oldest individuals disproportionately.
Glaucoma is not just one disease, rather, it is a spectrum of conditions that share a final common pathway of acquired, progressive deterioration of the neuronal components of the optic nerve. The neuronal death results in loss of vision once a sufficient number of individual nerves are destroyed.
Factors associated with the development of glaucoma and its progression have been identified and are in the process of being clarified. Elevated intraocular pressure (IOP) is the leading cause of glaucoma. Pressure is elevated because drainage of aqueous fluid from within the eye is impaired.
Current treatments for glaucoma center on reducing pressure in the eye by reducing the amount of aqueous fluid being produced or by enhancing the flow of fluid out of the eye by mechanical or other means. Topical agents that are presently in use include miotics, which increase the outflow of fluid (these include Isopto®Carpine, Ocusert®, Pilocar®, and Pilopine®); epinephrines, which also increase the outflow of fluid (these include Epifrin® and Propine®); beta-blockers, which reduce the amount of fluid (these include Betagan®, Betimol®, Betoptic®, Ocupress®, Optipranalol®, and Timoptic®); and carbonic anhydrase inhibitors and alpha-adrenergic agonists, which also reduce the amount of fluid (these include Alphagan®, Iopidine®, and Trusopt®). Prostaglandin analogs, which are also in use, increase the outflow of fluid through a secondary drainage route (these include Lumigan®, Rescula®, Travatan®, and Xalatan®). (Common oral medications include carbonic anhydrase inhibitors (such as Daranide®, Diamox®, and Neptazane®). These agents decrease aqueous humor inflow into the eye.)
Glaucoma patients may also suffer reduced blood flow to the optic nerve and neuronal tissue, and diminished resistance of the nerve tissue to damage, and the compliance of connective tissue surrounding and supporting the optic nerve. One agent, Memantine, is in phase III clinical trials (Allergan) as an agent that may prove to be neuroprotective.
The topical application of ophthamological drugs for the treatment of glaucoma requires penetration of the drug through the cornea and into the anterior chamber, which contains aqueous humor, which then drains into the conventional outflow pathway (trabecular meshwork and Schlemm's canal) and the uveal-scleral pathway (unconventional outflow pathway). Intraocular pressure is lowered by drugs acting in the trabecular meshwork/Schlemm's canal and the uveal-scleral pathway. Penetration of the drug through the cornea requires a balance of hydrophobic and hydrophilic characteristics. The drug must be sufficiently soluble in non-polar media to diffuse into the cornea and sufficiently soluble in polar (aqueous) media to diffuse out of the cornea into the aqueous humor.
Many drugs potentially useful for the treatment of glaucoma are carboxylic acids (e.g., phenoxyacetic acids or cinnaminic acids). Carboxylic acids are typically delivered in buffered aqueous solution; near neutral pH, carboxylic acids exist as the deprotonated carboxylate salt. Ionized carboxylate salts, while soluble in aqueous solution, will not penetrate the cornea. Such drugs can be delivered as pro-drug esters. The use of pro-drug esters, which are cleaved enzymatically (e.g., in the cornea) to regenerate the active compound, can enhance penetration of drug through the cornea into the anterior chamber.
Unfortunately, many esters are too hydrophobic (non-polar) to diffuse out of the relatively non-polar external layer of the cornea (corneal epithelium) and into the aqueous humor. Further complicating delivery, such compounds are often too insoluble to formulate in aqueous solutions.
The present invention provides a method of preparing derivatives of ophthamological drugs that contain a carboxyl group so as to overcome solubility and corneal penetration limitations associated with such drugs. The present approach results in the production of pro-drugs that can diffuse into the cornea of mammalian eyes but that are sufficiently water soluble to be released from the cornea into the aqueous humor. Pro-drugs of the invention are activated by esterases in the cornea, with the result that the active drug is present in the aqueous humor of the anterior chamber.